The Importance of Statistical Theory in Outlier Detection

We explore the performance of the outlier-sum statistic (Tibshirani and Hastie, Biostatistics 2007 8:2--8), a proposed method for identifying genes for which only a subset of a group of samples or patients exhibits differential expression levels. Our discussion focuses on this method as an example of how inattention to standard statistical theory can lead to approaches that exhibit some serious drawbacks. In contrast to the results presented by those authors, when comparing this method to several variations of the $t$-test, we find that the proposed method offers little benefit even in the most idealized scenarios, and suffers from a number of limitations including difficulty of calibration, high false positive rates owing to its asymmetric treatment of groups, poor power or discriminatory ability under many alternatives, and poorly defined application to one-sample settings. Further issues in the Tibshirani and Hastie paper concern the presentation and accuracy of their simulation results; we were unable to reproduce their findings, and we discuss several undesirable and implausible aspects of their results

Exploring the Benefits of Adaptive Sequential Designs in Time-to-Event Endpoint Settings

Sequential analysis is frequently employed to address ethical and financial issues in clinical trials. Sequential analysis may be performed using standard group sequential designs, or, more recently, with adaptive designs that use estimates of treatment effect to modify the maximal statistical information to be collected. In the general setting in which statistical information and clinical trial costs are functions of the number of subjects used, it has yet to be established whether there is any major efficiency advantage to adaptive designs over traditional group sequential designs. In survival analysis, however, statistical information (and hence efficiency) is most closely related to the observed number of events, while trial costs still depend on the number of patients accrued. As the number of subjects may dominate the cost of a trial, an adaptive design that specifies a reduced maximal possible sample size when an extreme treatment effect has been observed may allow early termination of accrual and therefore a more costefficient trial. We investigate and compare the tradeoffs between efficiency (as measured by average number of observed events required), power, and cost (a function of the number of subjects accrued and length of observation) for standard group sequential methods and an adaptive design that allows for early termination of accrual. We find that when certain trial design parameters are constrained, an adaptive approach to terminating subject accrual may improve upon the cost efficiency of a group sequential clinical trial investigating time-to-event endpoints. However, when the spectrum of group sequential designs considered is broadened, the advantage of the adaptive designs is less clear

Why do entrepreneurs open tech startups? A comparative study between Brazilian and foreign enterprises

This research identifies and compares the reasons that lead entrepreneurs to open a startup in Brazil or abroad along six factors: self-realization, financial, independence, innovation, roles, and recognition. Understanding differences between entrepreneurs in distinct settings may help designing better entrepreneurship policies and more effective support for nascent businesses, as well as providing better guidance to investors. Entrepreneurs who own technological startups answered an online questionnaire about the reasons for entrepreneurship through technological startups. Respondents ranked each statement using a Likert scale from (1) completely disagree to (5) completely agree. Of the respondents, 325 were Brazilian and 130 were foreigners. Results show that top-ranked reasons are mostly similar across groups, with four of the top five reasons being common. However, comparatively, they score several reasons differently. These results highlight the different reasons to enterprise between people from different countries, supporting the importance of studying the entrepreneurial phenomenon in emerging economies, which differ substantially from developed ones. They also may help conciliating conflicting results of the reasons to enterprise literature

Cryptic choice of conspecific sperm controlled by the impact of ovarian fluid on sperm swimming behavior

Despite evidence that variation in male–female reproductive compatibility exists in many fertilization systems, identifying mechanisms of cryptic female choice at the gamete level has been a challenge. Here, under risks of genetic incompatibility through hybridization, we show how salmon and trout eggs promote fertilization by conspecific sperm. Using in vitro fertilization experiments that replicate the gametic microenvironment, we find complete interfertility between both species. However, if either species’ ova were presented with equivalent numbers of both sperm types, conspecific sperm gained fertilization precedence. Surprisingly, the species’ identity of the eggs did not explain this cryptic female choice, which instead was primarily controlled by conspecific ovarian fluid, a semiviscous, protein-rich solution that bathes the eggs and is released at spawning. Video analyses revealed that ovarian fluid doubled sperm motile life span and straightened swimming trajectory, behaviors allowing chemoattraction up a concentration gradient. To confirm chemoattraction, cell migration tests through membranes containing pores that approximated to the egg micropyle showed that conspecific ovarian fluid attracted many more spermatozoa through the membrane, compared with heterospecific fluid or water. These combined findings together identify how cryptic female choice can evolve at the gamete level and promote reproductive isolation, mediated by a specific chemoattractive influence of ovarian fluid on sperm swimming behavior

Neurodevelopmental Roles of Semaphorin6A/PlexinA2 Signaling in Zebrafish

ABSTRACT A multitude of complex cellular changes are required throughout development in order for a single cell to transform into a fully functioning organism. Cellular events including proliferation, migration, and differentiation have to be carefully controlled in order for development to proceed correctly. In order to study such dynamic processes, in vivo models are often utilized. Using the zebrafish (Danio rerio) as a model system, we have investigated the role of an axon guidance signaling pair, Semaphorin6A (Sema6A) and PlexinA2 (PlxnA2), in neurodevelopment. A previous investigation into the developmental expression patterns of sema6A and plxnA2 in zebrafish, revealed overlapping expression in the developing eye. At this early stage, the cells in the optic vesicles are undifferentiated retinal precursor cells (RPCs) and therefore do not require Sema/Plxn signaling for their canonical axon guidance role. To understand what the function of this early expression was, we knocked down both sema6a and plxna2 and observed 1) a loss of cohesion of RPCs within optic vesicles, and 2) a decrease in RPC proliferation (Ebert et al., 2014). Because these phenotypes were seen at an early stage and given that many developmental processes are dependent on genetic regulation, we hypothesized that Sema6A/PlxnA2 signaling could be regulating transcription of downstream target genes. To investigate this, we performed a microarray experiment and uncovered 58 differentially regulated genes (Emerson et al., 2017a). Prior to our study, it was not known that Sema/Plxn signaling led to changes in gene transcription. In an effort to understand the contribution of identified candidate genes to early sema6A/plxnA2 knockdown phenotypes, candidate genes with predicted functions in proliferation and migration were investigated. First, we show that rasl11b is important for regulation of RPC proliferation in the developing optic vesicles. Second, we show that shootin-1 is important in optic vesicle migration, retinal pigmented epithelium formation and optic tract patterning. Furthermore, PlxnA2 regulation of shootin-1 levels is important in sensory and motor axon patterning and branching in the peripheral nervous system. Belonging to a large family of proteins with the ability to cross talk, Semas and Plxns rely on spatially and temporally differential expression patterns to perform their tissue-specific roles. Here, we used in situ hybridization to comprehensively uncover the neuronal expression patterns of the PlxnA family in the early developing zebrafish (Emerson et al., 2017b). In addition, we present for the first time that zebrafish have two genes for PlxnA1, A1a and A1b, which show divergent expression patterns. Semas and Plxns are critical for many aspects of development and together, this body of work provides further insight into the downstream signaling mechanisms and roles of these essential developmental signaling proteins

Post-copulatory opportunities for sperm competition and cryptic female choice provide no offspring fitness benefits in externally fertilizing salmon

There is increasing evidence that females can somehow improve their offspring fitness by mating with multiple males, but we understand little about the exact stage(s) at which such benefits are gained. Here, we measure whether offspring fitness is influenced by mechanisms operating solely between sperm and egg. Using externally-fertilising and polyandrous Atlantic salmon (Salmo salar), we employed split-clutch and split-ejaculate in vitro fertilisation experiments to generate offspring using designs that either denied or applied opportunities for sperm competition and cryptic female choice. Following fertilisations, we measured 140 days of offspring fitness after hatch, through growth and survival in hatchery and near-natural conditions. Despite an average composite mortality of 61%, offspring fitness at every life stage was near-identical between groups fertilised under the absence versus presence of opportunities for sperm competition and cryptic female choice. Of the 21,551 and 21,771 eggs from 24 females fertilised under monandrous versus polyandrous conditions, 68% versus 67.8% survived to the 100-day juvenile stage; sub-samples showed similar hatching success (73.1% versus 74.3%), had similar survival over 40 days in near-natural streams (57.3% versus 56.2%), and grew at similar rates throughout. We therefore found no evidence that gamete-specific interactions allow offspring fitness benefits when polyandrous fertilisation conditions provide opportunities for sperm competition and cryptic female choice

Detecting Differential Gene Expression in Subgroups of a Disease Population

In many disease settings, it is likely that only a subset of the disease population will exhibit certain genetic or phenotypic differences from the healthy population. Therefore, when seeking to identify genes or other explanatory factors that might be related to the disease state, we might expect a mixture distribution of the variable of interest in the disease group. A number of methods have been proposed for performing tests to identify situations for which only a subgroup of samples or patients exhibit differential expression levels. Our discussion here focuses on how inattention to standard statistical theory can lead to approaches that exhibit some serious drawbacks. We present and discuss several approaches motivated by theoretical derivations and compare to an ad hoc approach based upon identification of outliers. We find that the outlier-sum statistic proposed by Tibshirani and Hastie offers little benefit over a t-test even in the most idealized scenarios and suffers from a number of limitations including difficulty of calibration, lack of robustness to underlying distributions, high false positive rates owing to its asymmetric treatment of groups, and poor power or discriminatory ability under many alternatives.This is the publisher’s final pdf. The published article is copyrighted by Walter de Gruyter GmbH and can be found at: http://www.degruyter.com/view/j/ijb.Keywords: microarray, t-test, gene expression analysis, efficiency, hypothesis testin

Types of Technological Entrepreneurs: a Study in a Large Emerging Economy

This study identifies the profiles of technological entrepreneurs. Understanding what drives entrepreneurs can help policy design to incentivize entrepreneurship, support the development of better assistance for nascent businesses, and facilitate the matching between investors’ and entrepreneurs’ interests. Through the application of an online questionnaire, 325 Brazilian owners of technological startups answered their reasons to enterprise. The data was processed using Ward’s hierarchical clustering algorithm, generating four distinct clusters. The first, financial success entrepreneurs, are concerned about financial outcomes of their startups. The new challenges group seeks self-realization, innovation, and independence by means of their enterprises. Leaders are driven by the will to lead and motivate others, relegating other factors. Finally, there are pessimistic entrepreneurs, who rank all reasons lower than other entrepreneurs. These results highlight that even within the class of technological entrepreneurs, from the same country, there are sizeable groups with different factors regarding reasons to enterprise, shedding some light on conflicting results in the entrepreneurial motivation literature

Building a Bridge to Next Generation DH Services in Libraries with a Campus Needs Assessment

This poster reports on a needs assessment for digital humanities library services undertaken at large research university in order to provide a basis for transition to a next phase of Digital Humanities (DH) support at a library supporting a growing amount of DH work on campus. It reports key findings and how the library services will evolve to meet needs identified on campus. The full report on which this presentation is based is available at http://hdl.handle.net/2142/100081Ope